Sha Ming-Quan, Zhao Xiao-Li, Li Liang, Li Li-Hui, Li Yi, Dong Tian-Geng, Niu Wei-Xin, Jia Li-Jun, Shao Rong-Guang, Zhen Yong-Su, Wang Zhen
Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Cancer Institute, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Cell Death Dis. 2016 Nov 24;7(11):e2486. doi: 10.1038/cddis.2016.383.
Lidamycin (LDM) is a novel member of the enediyne antibiotics identified in China with potent antitumor activity. However, it remains unclear whether LDM has potential molecular targets that may affect its antitumor activity. Enhancer of zeste homolog 2 (EZH2) functions as a histone lysine methyltransferase and mediates trimethylation on histone 3 lysine 27 (H3K27me3). High EZH2 level is found to be positively correlated with the aggressiveness, metastasis and poor prognosis of cancer. Here, we aim to study the role of EZH2 in LDM-induced senescence, as well as in the cytotoxicity of LDM in human colon cancer cells. LDM is found to be relatively more potent in inhibiting the colon cancer cells harboring high EZH2 level and induces irreversible cellular senescence at IC dose range, as evidenced by senescence-associated β-galactosidase staining, cell cycle arrest and molecular changes of senescence regulators including p21 in HCT116 and SW620 cells. More importantly, LDM is found to markedly inhibit EZH2 expression at both protein and mRNA levels upon the induction of p21 and cellular senescence. LDM also selectively inhibits EZH2 expression as compared with other histone lysine methyltransferases. Knockdown of p21 with siRNAs abolishes LDM-induced senescence, whereas EZH2 knockdown markedly increases p21 expression and causes senescent phenotype. Enrichment of both EZH2 and H3K27me3 levels in the p21 promoter region is reduced by LDM. Moreover, EZH2 overexpression reduces cellular senescence, p21 expression and DNA damage response upon LDM exposure. LDM also demonstrates potent antitumor efficacy in xenografted animal models. Collectively, our work provides first demonstration that EZH2 may mediate, at least partially, the senescence-inducing effects of LDM by regulating p21 expression and DNA damage effect. Thus, EZH2 may serve as a potential target and biomarker to indicate the clinical efficacy of the potent enediyne antitumor drug.
力达霉素（LDM）是在中国发现的具有强大抗肿瘤活性的烯二炔类抗生素中的一个新成员。然而，LDM是否具有可能影响其抗肿瘤活性的潜在分子靶点仍不清楚。zeste同源物2增强子（EZH2）作为一种组蛋白赖氨酸甲基转移酶，介导组蛋白3赖氨酸27（H3K27me3）的三甲基化。发现高EZH2水平与癌症的侵袭性、转移和不良预后呈正相关。在此，我们旨在研究EZH2在LDM诱导的衰老以及LDM对人结肠癌细胞的细胞毒性中的作用。发现LDM在抑制具有高EZH2水平的结肠癌细胞方面相对更有效，并在IC剂量范围内诱导不可逆的细胞衰老，衰老相关β-半乳糖苷酶染色、细胞周期阻滞以及衰老调节因子（包括HCT116和SW620细胞中的p21）的分子变化证明了这一点。更重要的是，在诱导p21和细胞衰老后，发现LDM在蛋白质和mRNA水平上均显著抑制EZH2表达。与其他组蛋白赖氨酸甲基转移酶相比，LDM还选择性地抑制EZH2表达。用小干扰RNA敲低p21可消除LDM诱导的衰老，而敲低EZH2则显著增加p21表达并导致衰老表型。LDM降低了p21启动子区域中EZH2和H3K27me3水平的富集。此外，EZH2过表达可降低LDM暴露后的细胞衰老、p21表达和DNA损伤反应。LDM在异种移植动物模型中也显示出强大的抗肿瘤功效。总的来说，我们的工作首次证明EZH2可能至少部分地通过调节p21表达和DNA损伤效应来介导LDM的衰老诱导作用。因此，EZH2可能作为一个潜在的靶点和生物标志物来指示这种强大的烯二炔类抗肿瘤药物的临床疗效。
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